Roberson et al. demonstrate that a protein linked to human disease regulates ciliary membrane composition by organizing the organelle’s transition zone.

The Meckel syndrome (MKS) complex assembles at the transition zone between the ciliary basal body and axoneme, where it controls the localization of ciliary membrane proteins. Mutations in the genes encoding MKS complex proteins disrupt ciliary membrane composition and cause MKS, a human disease characterized by cystic kidneys, polydactyly, and defects in bile duct formation. A transmembrane protein called Tmem231 binds to the MKS complex protein B9d1, but its contribution to the assembly and function of the complex is unclear.

Mutations in human TMEM231 have also been linked to MKS, but Tmem231 knockout mice die too early in embryogenesis to display any hallmarks of the disease. Roberson et al. knocked out Tmem231 in a mixed genetic background, which allowed the animals to survive long enough to develop MKS-like symptoms. MKS complex components, including B9d1, failed to assemble at the ciliary transition zone in these mice, resulting in the loss of key signaling proteins, such as Arl13b and Inpp5e, from the ciliary membrane.

Roberson et al. identified several additional TMEM231 mutations, not only in MKS patients but also in two siblings with orofaciodigital syndrome type 3. All of these mutations disrupted the MKS complex’s localization and function in cultured fibroblasts. Senior author Jeremy Reiter now wants to understand how the complex regulates ciliary composition and to investigate why the symptoms of MKS are more severe than those of orofaciodigital syndrome type 3.

, et al
J. Cell Biol.

Author notes

Text by Ben Short